Los Alamos research intriguing but caution is urged

Researchers at Los Alamos National Laboratory, using analytical tools repurposed from studies of HIV and influenza, found mutations in SARS-CoV-2, including one that they think could increase its transmissibility.

That change, a mutation dubbed D614G on the viral spike protein, is of “urgent concern; it began spreading in Europe in early February, and when introduced to new regions it rapidly becomes the dominant form,” the investigators wrote on the pre-print site bioRxiv.

The best explanation of the spread is that variants with the mutation are more transmissible than earlier versions with a different genetic sequence, according to a team led by Bette Korber, PhD, a computational chemist well known for her work on HIV vaccines. A vaccine candidate developed by Korber and colleagues is in clinical trials in Africa.

But others cautioned that the analysis has not been peer-reviewed and should be taken with a degree of caution.

“There is a lot of speculation here. They have no experimental verification,” Peter Hotez, PhD, of the Texas Children’s Hospital Center for Vaccine Development in Houston, told the Los Angeles Times.

In any case, as the investigators themselves noted, increased transmissibility does not necessarily imply increased danger; a sub-analysis in the report showed no rise in the risk of severe illness linked to the mutated sequence, compared with its predecessor.

Nonetheless, they argued that it’s important to track changes in SARS-CoV-2 in order to avoid being blindsided by mutations that might limit the effectiveness of drugs or vaccines or might allow the virus to slip past immunity acquired to previous versions.

The D614G mutation is a single nucleotide polymorphism — a single letter of genetic code is changed — and strains bearing the mutation, dubbed G614, emerged after the so-called D614 version but quickly became the dominant form found in many parts of the world, the investigators said.

Structural analysis, they argued, suggests “several ways” G614 could have outcompeted the earlier version — better binding to its cellular receptor, better fusion to the target cell, or an increase in what’s called “antibody-dependent enhancement” of virulence.

The altered spike protein might also have reduced sensitivity to neutralizing antibodies against earlier forms, potentially making people susceptible to a second infection.

The spike protein is the key to the ability of SARS-CoV-2 to infect cells; drug and vaccine candidates are aimed at it but might miss their targets if it changes in unexpected ways, the researchers argued.

But it’s unlikely that a single point mutation will “have any impact on imaginary drugs with unknown mechanisms of action. Nor really for vaccines,” according to Bill Hanage, PhD, of Harvard T.H. Chan School of Public Health.

Among other things, Hanage wrote on Twitter, it’s important to remember that any drug or vaccine will be tested against whatever version of the virus is circulating. “The virus would have to be awfully lucky to have landed on the escape mutation for all these vaccines so early,” he argued.

He also argued that, since few people have any natural immunity to the virus, there is little or no selection pressure to cause escape mutations.

The paper, titled “Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2,” is essentially the first formal report on an early warning system intended to follow the evolution of the viral spike protein.

SARS-CoV-2 sequences collected from around the world pile up at a “furious rate” in the Global Initiative for Sharing All Influenza Data (GISAID) database, the investigators wrote, providing a tsunami of information.

Korber and colleagues devised an automated system that provides real-time critical analysis on the evolution of the spike protein, meant to allow researchers to generate visualizations and summaries of the data.

In addition, they can perform structural analyses or the effect of changes, which can then lead to experimental studies.

The system, at www.cov.lanl.gov, was meant to be live when the paper appeared but was still not functioning May 5; Korber said in a comment on the paper that some expected approvals were not yet forthcoming.

Michael Smith, Contributing Writer, BreakingMED™

Cat ID: 190

Topic ID: 79,190,730,933,190,926,192,927,151,590,928